Beyond the Channels: Adhesion Functions of Aquaporin 0 and Connexin 50 in Lens Development

Abstract

Lens, an avascular tissue involved in light transmission, generates an internal microcirculatory system to promote ion and fluid circulation, thus providing nutrients to internal lens cells and excreting the waste. This unique system makes up for the lack of vasculature and distinctively maintains lens homeostasis and lens fiber cell survival through channels of connexins and other transporters. Aquaporins (AQP) and connexins (Cx) comprise the majority of channels in the lens microcirculation system and are, thus, essential for lens development and transparency. Mutations of AQPs and Cxs result in abnormal channel function and cataract formation. Interestingly, in the last decade or so, increasing evidence has emerged suggesting that in addition to their well-established channel functions, AQP0 and Cx50 play pivotal roles through channel-independent actions in lens development and transparency. Specifically, AQP0 and Cx50 have been shown to have a unique cell adhesion function that mediates lens development and transparency. Precise regulation of cell-matrix and cell-cell adhesion is necessary for cell migration, a critical process during lens development. This review will provide recent advances in basic research of cell adhesion mediated by AQP0 and Cx50.

Keywords: aquaporin; cell adhesion; connexin; lens cell differentiation; lens development; lens transparency.

FIGURE 1

Illustration showing the basic structure of channels formed by aquaporins and connexins. Aquaporins and connexins share similar membrane topologies consisting of transmembrane domains connected by extracellular and cytoplasmic loops; both the amino- and carboxy-termini are intracellular. An AQP0 monomer consists of six transmembrane α-helices and two half helices connected by five loops. Each AQP monomer contains an independent water pore. AQP0 tetramers forms wavy thin junctions or square array junctions between adjacent cells. The dark blue arrow represents the pore which transports water (left upper panel). The amino acid residues (Arg33, Arg113, Arg187, His40, His112, His201, Pro109, Pro110, and Pro123) located in the extracellular loop domain involved in the cell adhesion are labeled (left lower panel). The membrane topology of a connexin consists of four transmembrane domains, two extracellular loops and one cytoplasmic loop (right lower panel). Connexin channels provide a pathway for the intracellular and intercellular exchange of ions, small metabolites, and second messengers (dark blue arrow). A hemichannel (also known as connexons) is formed by six connexins that contains a pore in the center, and a hemichannel dock with the other hemichannel of adjacent cells to form a functional intercellular channel termed gap junction channel (right upper panel).

FIGURE 2

Impairment of cell adhesive function mediated by AQP0 or Cx50 mutation disrupts the organization of lens fibers. In lens fibers, AQP0 and Cx50, primarily located at the short side and broad side of mature lens fibers, respectively, directly interact with each other, and function like “glue” to mediate the cell–cell adhesion, which maintains lens fiber integrity and organization (left upper and lower panels). The hexagon shape indicates cross-section of lens fiber cells. The lenses showing mutations of Cx50 or AQP0 lose cell–cell adhesion in fiber cells, resulting in the impairment of epithelial cell proliferation, increased intercellular spaces and disorganization of lens fibers, which consequently leads to loss of lens elasticity and transparency (right upper and lower panels). The complete loss of Cx50 or AQP0 (Cx50 KO or AQP0 KO) lead to a similar levels of fiber cell disruption.